The preparation and use of compounds, such as N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (or N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) and salts thereof, in the treatment of depression is described in British Patent Specification 2098602. The use of compounds such as N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof in the treatment of Parkinson""s disease is described in European Patent Number 282206. The use of compounds such as N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof in the treatment of cerebral function disorders is described in U.S. Pat. No. 4,939,175. The use of N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride in the treatment of obesity is described in European Patent Number 397831. A particularly preferred form of this compound is N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate (sibutramine hydrochloride monohydrate) which is described in European Patent Number 230742. The use of N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof for improving the glucose tolerance of humans having Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus is described in published PCT application WO95/20949.
All of the above documents are incorporated herein by reference.
The use of sibutramine as an insulin sensitiser is disclosed in WO98/11884. The use of sibutramine in lowering uric acid levels is disclosed in WO98/13033. The use of sibutramine in lowering lipid levels is disclosed in WO98,13034.
This invention relates to the (+)-enantiomer of Sibutramine, which is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine, and pharmaceutically acceptable salts thereof, to their use in the treatment of obesity and depression, to formulations containing these compounds and to methods for their preparation.
The present invention provides a method of treating any of the indications previously disclosed as being treatable by racemic sibutramine in any of the above documents comprising administering to a mammal, particularly a human, in need thereof a therapeutically effective amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-enantiomer.
In particular (+)-sibutramine is useful in the treatment of depression, obesity, Parkinson""s disease, cerebral function disorders and diabetes.
The present invention provides a method of treating depression in a human which comprises administering to a human in need of antidepressant therapy, an amount of (+)-sibutramine, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate depression.
In another aspect the present invention provides a method for treating obesity or weight gain in a human which comprises administering to a human in need of a reduction in weight, an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate obesity or weight gain.
In yet another aspect the present invention provides a method of treating disorders ameliorated by inhibition of neuronal monoamine reuptake in a human which comprises administering to a human in need of such treatment an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate said disorders. Preferably said monoamine is dopamine. Preferably said disorder is Parkinson""s disease.
In yet another aspect the present invention provides a method for treating cerebral function disorders in humans which comprises administering to a human an amount of (+)-sibutramine, or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate cerebral function disorders. In a preferred embodiment the cerebral function disorder is caused by a cerebrovascular disease. In another preferred embodiment the cerebral function disorder is selected from the group consisting of senile dementia, Alzheimer""s type dementia, memory loss and amnesia/amnestic syndrome. Preferably the cerebrovascular disease is selected from the group consisting of cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis and head injuries.
The above inventions provide in preferred embodiments methods of treating depression, obesity, weight gain, disorders ameliorated by inhibition of neuronal monoamine reuptake or cerebral function disorders in a human in which said amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, is sufficient to alleviate the said disease or disorder but insufficient to cause adverse effects associated with the administration of racemic sibutramine.
Examples of pharmaceutically acceptable salts of (+)-sibutramine include the hydrochloride, hydrobromide, sulphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate [e.g. (+)-tartrate, (xe2x88x92)-tartrate or mixtures thereof including racemic mixtures], succinate, benzoate, benzenesulphonate, camphorsulphonate, gluconate, lactate, malate, mandelate, pamoate, phosphate, p-toluenesulphonate and salts with amino acids such as glutamic acid. Preferably the salt is the hydrochloride salt.
In another aspect the present invention provides a composition for the treatment of depression in a human which comprises an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate depression.
In a further aspect the present invention provides a composition for the treatment of depression in a human wherein said amount of (+)-sibutramine, or a pharmaceutically acceptable salt thereof, is sufficient to treat depression but insufficient to cause adverse effects associated with the administration of racemic sibutramine.
In another aspect the present invention provides a composition for treating obesity or weight gain in a human which comprises an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate obesity or weight gain.
In a further aspect the present invention provides a composition for treating weight disorders in a human wherein said amount is sufficient to alleviate obesity or weight gain in a human but insufficient to cause adverse effects associated with administration of racemic sibutramine.
In another aspect the present invention provides a composition for the treatment of disorders ameliorated by inhibition of neuronal monoamine reuptake in a human which comprises an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate said disorders.
In a further aspect the present invention provides a composition for the treatment of disorders ameliorated by inhibition of neuronal monoamine reuptake in a human wherein said amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, is sufficient to treat said disorders but insufficient to cause adverse effects associated with the administration of racemic sibutramine.
In another aspect the present invention provides a composition for treating cerebral function disorders, which comprises an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (xe2x88x92)-stereoisomer, said amount being sufficient to alleviate cerebral function disorders.
In a further aspect the present invention provides a composition for treating cerebral function disorders wherein said amount of (+)-sibutramine or a pharmaceutically salt thereof, substantially free of its (xe2x88x92)-stereoisomer, is sufficient to treat cerebral function disorders but insufficient to cause the adverse effects associated with the administration of racemic sibutramine.
Preferably the above compositions comprise (+)-sibutramine and a pharmaceutically acceptable diluent or carrier. In the following the term active compound means (+)-sibutramine or a pharmaceutically acceptable salt thereof.
The active compound may be administered in any of the known pharmaceutical dosage forms. The amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range from 0.1 to 100 mg, preferably 1 to about 60 mg per day, more preferably from about 2 mg to about 50 mg per day and most preferably from about 5 mg to about 45 mg per day. Especially preferred dosages are 5 mg, 10 mg, 15 mg and 20 mg per day given in one or more doses.
Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions. The excipients used in the preparation of these compositions are the excipients known in the pharmacist""s art. Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods. The tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound. The tablets and capsules may conveniently. each contain 0.1 to 100 mg, preferably 1 to about 60 mg per day, more preferably from about 2 mg to about 50 mg per day and most preferably from about 5 mg to about 45 mg per day. Especially preferred dosages are 5 mg, 10 mg, 15 mg and 20 mg per day given in one or more doses.
Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy-methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil. The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion. The granules may contain disintegrants, e.g. an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
The active compound may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol. Alternatively the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
The active compound may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity. Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
The active compound used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused. The support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
The term xe2x80x9cadverse effectsxe2x80x9d as used herein includes, but is not limited to increases in heart rate, increases in blood pressure including systolic blood pressure, increased psychomotor activity, dry mouth, tension and nervousness.
The term xe2x80x9csubstantially free of its (xe2x88x92)-stereoisomerxe2x80x9d, as used herein, means that the composition contains a greater proportion of the (+)-stereoisomer of sibutramine in relation to the (xe2x88x92)-isomer of sibutramine. The term xe2x80x9csubstantially free of its (xe2x88x92)-stereoisomerxe2x80x9d includes a composition containing an amount of the (+)-stereoisomer of sibutramine in relation to the (xe2x88x92)-isomer of sibutramine such that the composition can perform its intended function, e.g., of treating the selected indication, e.g., treating obesity, weight gain, and/or depression. In a preferred embodiment of the present invention the term xe2x80x9csubstantially free of its (xe2x88x92)-stereoisomerxe2x80x9d as used herein means that the composition contains at least 90% by weight of (+)-sibutramine and 10% by weight or less of (xe2x88x92)-sibutramine. In the most preferred embodiment, the term xe2x80x9csubstantially free of its (xe2x88x92stereoisomerxe2x80x9d means that the composition contains at least 99% by weight of (+)-sibutramine and 1% or less of (xe2x88x92)-sibutramine. In another preferred embodiment, the term xe2x80x9csubstantially free of its (xe2x88x92)-stereoisomerxe2x80x9d as used herein means that the composition contains 100% by weight of the (+)-isomer of sibutramine. The above percentages are based on the total amount of sibutramine present in the composition. The terms xe2x80x9csubstantially optically pure (+)-sibutraminexe2x80x9d, xe2x80x9coptically pure (+)-sibutraminexe2x80x9d and xe2x80x9c(+)-isomer of sibutraminexe2x80x9d are also encompassed by the above described amounts.
The invention is illustrated by the following Examples which are given by way of example only. The final product of each of these Examples was characterised by one or more of the following procedures: gas-liquid chromatography; high performance liquid chromatography; elemental analysis, nuclear magnetic resonance spectroscopy and infrared spectroscopy.